Ana Marcia Delattre

Evaluation of chronic omega-3 fatty acids supplementation on behavioral and neurochemical alterations in 6-hydroxydopamine-lesion model of Parkinson's disease

Omega-3 polyunsaturated fatty acids (omega-3 PUFAs) have been widely associated to beneficial effects over different neuropathologies, but only a few studies associate them to Parkinsons disease (PD). Rats were submitted to chronic supplementation (21-90 days of life) with fish oil, rich in omega-3 PUFAs, and were uni- or bilaterally lesioned with 4microg of the neurotoxin 6-hydroxydopamine (6-OHDA) in the medial forebrain bundle. Although lipid incorporation was evidenced in neuronal membranes, it was not sufficient to compensate motor deficits induced by 6-OHDA. In contrast, omega-3 PUFAs were capable of reducing rotational behavior induced by apomorphine, suggesting neuroprotection over dyskinesia. The beneficial effects of omega-3 PUFAs were also evident in the maintenance of thiobarbituric acid reactive substances index from animals lesioned with 6-OHDA similar to levels from SHAM and intact animals. Although omega-3 PUFAs did not modify the tyrosine hydroxylase immunoreactivity in the substantia nigra pars compacta and in the ventral tegmental area, nor the depletion of dopamine (DA) and its metabolites in the striatum, DA turnover was increased after omega-3 PUFAs chronic supplementation. Therefore, it is proposed that omega-3 PUFAs action characterizes the adaptation of remaining neurons activity, altering striatal DA turnover without modifying the estimated neuronal population.

Motor and Non-Motor Features of Parkinson’s Disease – A Review of Clinical and Experimental Studies

Classically, Parkinsons disease (PD) is considered to be a motor system affliction and its diagnosis is based on the presence of a set of cardinal motor signs (e.g. rigidity, bradykinesia, rest tremor and postural reflex disturbance). However, there is considerable evidence showing that non-motor alterations (e.g. anxiety, depression, sleep, gastrointestinal and cognitive functions) precede the classical motor symptoms seen in PD. The management of these nonmotor symptoms remains a challenge. A pattern of regional neurodegeneration that varies considerably depending upon the neuronal population affected may explain the different symptoms. In fact, differential mechanisms of neuronal vulnerability within the substantia nigra pars compacta (SNpc) suggests that factors other than location contribute to the susceptibility of these neurons. In this review we discuss how these factors interact to ultimately target the SNpc. Remarkably, this region consists of approximately 95% of the tyrosine hydroxylase (TH)-immunoreactive neurons in both human and rat brains, and consequently this implicates elevated levels of dopamine metabolites, free radicals and other hazard species in these neurons. An understanding of how these factors promote neuronal death may be useful for the development of novel neuroprotective and/or neurorestorative strategies for PD.

Fish oil improves anxiety-like, depressive-like and cognitive behaviors in olfactory bulbectomised rats

Depression is increasingly present in the population, and its pathophysiology and treatment have been investigated with several animal models, including olfactory bulbectomy (Obx). Fish oil (FO) supplementation during the prenatal and postnatal periods decreases depression‐like and anxiety‐like behaviors. The present study evaluated the effect of FO supplementation on Obx‐induced depressive‐like behavior and cognitive impairment. Female rats received supplementation with FO during habituation, mating, gestation, and lactation, and their pups were subjected to Obx in adulthood; after the recovery period, the adult offspring were subjected to behavioral tests, and the hippocampal levels of brain‐derived neurotrophic factor (BDNF), serotonin (5‐HT) and the metabolite 5‐hydroxyindoleacetic (5‐HIAA) were determined. Obx led to increased anxiety‐like and depressive‐like behaviors, and impairment in the object location task. All behavioral changes were reversed by FO supplementation. Obx caused reductions in the levels of hippocampal BDNF and 5‐HT, whereas FO supplementation restored these levels to normal values. In control rats, FO increased the hippocampal level of 5‐HT and reduced that of 5‐HIAA, indicating low 5‐HT metabolism in this brain region. The present results indicate that FO supplementation during critical periods of brain development attenuated anxiety‐like and depressive‐like behaviors and cognitive dysfunction induced by Obx. These results may be explained by increased levels of hippocampal BDNF and 5‐HT, two major regulators of neuronal survival and long‐term plasticity in this brain structure.

Does Parkinson's disease and type-2 diabetes mellitus present common pathophysiological mechanisms and treatments?

Parkinsons disease (PD) is the second most common neurodegenerative disease afflicting about 1% of people over 65 years old and 4-5% of people over 85 years. It is proposed that a cascade of deleterious factors is set in motion within that neuron made not of one, but rather of multiple factors such as free radicals, excitotoxicity, neuroinflammation, and apoptosis to cite only some of the most salient. In this scenario, chronic systemic inflammation, as well as impaired mitochondrial metabolism, have also been suspected of playing a role in the development of type-2 diabetes, and the possibility of a shared pathophysiology of PD and type-2 diabetes has been proposed. The discussion about the interactions between PD and type-2 diabetes mellitus began in the 1960s and there is still controversy. Insulin and dopamine may exert reciprocal regulation hence; hypoinsulinemia induced by streptozotocin decreased the amounts of dopamine transporter and tyrosine hydroxylase transcripts in the substantia nigra pars compacta. Accordingly, dopamine depletion in the striatum is able to decreases insulin signaling in basal ganglia, indicating that, perhaps, PD may be considered as a risk factor for the development of type-2 diabetes mellitus. In this sense, it is described that peroxisome proliferator-activated receptor-γ, ATP-sensitive K(+) channels, AMP-activated protein kinase, glucagon-like peptide-1 and dipeptidyl peptidase-4 are important therapeutic targets for PD and reinforces the association with diabetes. Therefore, the objective of the present review is to contextualize the mutual pathophysiological interactions between PD and type-2 diabetes mellitus, as well as the potential common treatments.

Lesion of the subthalamic nucleus reverses motor deficits but not death of nigrostriatal dopaminergic neurons in a rat 6-hydroxydopamine-lesion model of Parkinson's disease

The objective of the present study was to determine whether lesion of the subthalamic nucleus (STN) promoted by N-methyl-D-aspartate (NMDA) would rescue nigrostriatal dopaminergic neurons after unilateral 6-hydroxydopamine (6-OHDA) injection into the medial forebrain bundle (MFB). Initially, 16 mg 6-OHDA (6-OHDA group) or vehicle (artificial cerebrospinal fluid - aCSF; Sham group) was infused into the right MFB of adult male Wistar rats. Fifteen days after surgery, the 6-OHDA and SHAM groups were randomly subdivided and received ipsilateral injection of either 60 mM NMDA or aCSF in the right STN. Additionally, a control group was not submitted to stereotaxic surgery. Five groups of rats were studied: 6-OHDA/NMDA, 6-OHDA/Sham, Sham/NMDA, Sham/Sham, and Control. Fourteen days after injection of 6-OHDA, rats were submitted to the rotational test induced by apomorphine (0.1 mg/kg, ip) and to the open-field test. The same tests were performed again 14 days after NMDA-induced lesion of the STN. The STN lesion reduced the contralateral turns induced by apomorphine and blocked the progression of motor impairment in the open-field test in 6-OHDA-treated rats. However, lesion of the STN did not prevent the reduction of striatal concentrations of dopamine and metabolites or the number of nigrostriatal dopaminergic neurons after 6-OHDA lesion. Therefore, STN lesion is able to reverse motor deficits after severe 6-OHDA-induced lesion of the nigrostriatal pathway, but does not protect or rescue dopaminergic neurons in the substantia nigra pars compacta.

REM sleep deprivation generates cognitive and neurochemical disruptions in the intranigral rotenone model of Parkinson's disease.

The recently described intranigral rotenone model of Parkinsons disease (PD) in rodents provides an interesting model for studying mechanisms of toxin‐induced dopaminergic neuronal injury. The relevance of this model remains unexplored with regard to sleep disorders that occur in PD. On this basis, the construction of a PD model depicting several behavioral and neurochemical alterations related to sleep would be helpful in understanding the association between PD and sleep regulation. We performed bilateral intranigral injections of rotenone (12 μg) on day 0 and the open‐field test initially on day 20 after rotenone. Acquisition phase of the object‐recognition test, executed also during day 20, was followed by an exact period of 24 hr of rapid eye movement (REM) sleep deprivation (REMSD; day 21). In the subsequent day (22), the rats were re‐exposed to the open‐field test and to the object‐recognition test (choice phase). After the last session of behavioral tests, the rat brains were immediately dissected, and their striata were collected for neurochemical purposes. We observed that a brief exposure to REMSD was able to impair drastically the object‐recognition test, similarly to a nigrostriatal lesion promoted by intranigral rotenone. However, the combination of REMSD and rotenone surprisingly did not inflict memory impairment, concomitant with a moderate compensatory mechanism mediated by striatal dopamine release. In addition, we demonstrated the existence of changes in serotonin and noradrenaline neurotransmissions within the striatum mostly as a function of REMSD and REMSD plus rotenone, respectively.

Maternal Omega-3 Supplement Improves Dopaminergic System in Pre- and Postnatal Inflammation-Induced Neurotoxicity in Parkinson's Disease Model.

Evidence suggests that idiopathic Parkinson’s disease (PD) is the consequence of a neurodevelopmental disruption, rather than strictly a consequence of aging. Thus, we hypothesized that maternal supplement of omega-3 polyunsaturated fatty acids (ω-3 PUFA) may be associated with neuroprotection mechanisms in a self-sustaining cycle of neuroinflammation and neurodegeneration in lipopolysaccharide (LPS)-model of PD. To test this hypothesis, behavioral and neurochemical assay were performed in prenatally LPS-exposed offspring at postnatal day 21. To further determine whether prenatal LPS exposure and maternal ω-3 PUFAs supplementation had persisting effects, brain injury was induced on PN 90 rats, following bilateral intranigral LPS injection. Pre- and postnatal inflammation damage not only affected dopaminergic neurons directly, but it also modified critical features, such as activated microglia and astrocyte cells, disrupting the support provided by the microenvironment. Unexpectedly, our results failed to show any involvement of caspase-dependent and independent apoptosis pathway in neuronal death mechanisms. On the other hand, learning and memory deficits detected with a second toxic exposure were significantly attenuated in maternal ω-3 PUFAs supplementation group. In addition, ω-3 PUFAs promote beneficial effect on synaptic function, maintaining the neurochemical integrity in remaining neurons, without necessarily protect them from neuronal death. Thus, our results suggest that ω-3 PUFAs affect the functional ability of the central nervous system in a complex way in a multiple inflammation-induced neurotoxicity animal model of PD and they disclose new ways of understanding how these fatty acids control responses of the brain to different challenges.

Neuroprotective effect of omega-3 polyunsaturated fatty acids in the 6-OHDA model of Parkinson's disease is mediated by a reduction of inducible nitric oxide synthase

Objective: Parkinsons disease (PD) is characterized by deterioration of the nigrostriatal system and associated with chronic neuroinflammation. Glial activation has been associated with regulating the survival of dopaminergic neurons and is thought to contribute to PD through the release of proinflammatory and neurotoxic factors, such as reactive nitric oxide (NO) that triggers or exacerbates neurodegeneration in PD. Polyunsaturated fatty acids (PUFAs) exert protective effects, including antiinflammatory, antiapoptotic, and antioxidant activity, and may be promising for delaying or preventing PD by attenuating neuroinflammation and preserving dopaminergic neurons. The present study investigated the effects of fish oil supplementation that was rich in PUFAs on dopaminergic neuron loss, the density of inducible nitric oxide synthase (iNOS)-immunoreactive cells, and microglia and astrocyte reactivity in the substantia nigra pars compacta (SNpc) and striatal dopaminergic fibers. Methods: The animals were supplemented with fish oil for 50 days and subjected to unilateral intrastriatal 6-hydroxydopamine (6-OHDA)-induced lesions as a model of PD. Results: Fish oil mitigated the loss of SNpc neurons and nerve terminals in the striatum that was caused by 6-OHDA. This protective effect was associated with reductions of the density of iNOS-immunoreactive cells and microglia and astrocyte reactivity. Discussion: These results suggest that the antioxidant and antiinflammatory properties of fish oil supplementation are closely related to a decrease in dopaminergic damage that is caused by the 6-OHDA model of PD. GRAPHICAL ABSTRACT

Fish Oil has Beneficial Effects on Behavior Impairment and Oxidative Stress in Rats Subjected to a Hepatic Encephalopathy Model

Hepatic encephalopathy (HE) is a severe neuropsychiatric complication of liver failure, in which there is injury to brain cells, particularly neurons and glia. Brain cells and their function are greatly influenced by omega-3 polyunsaturated fatty acids, essential components of cell membrane phospholipids in the brain that are crucial to normal function. This study assessed the effect of chronic fish oil (FO) supplementation (rich in omega-3 polyunsaturated fatty acids) on behavior and oxidative stress of Wistar rats subjected to HE due to a liver failure caused by thioacetamide (TAA) intoxication. The FO supplementation started in an early phase of brain development, that is, at the 21st day of life, and extended to the 122th day of life. The results indicated that cognitive function, specifically spatial memory, was markedly affected in the group that received TAA. Most notably, the ill effects caused by TAA administration were counteracted by FO supplementation. In addition to behavioral improvements, FO also promoted reduction in levels of thiobarbituric acid-reactive substances and superoxide dismutase activity in hippocampus and cerebral cortex. In summary, FO protected against spatial memory deficits and oxidative stress caused by HE in rats subjected to liver lesion due to TAA intoxication. Further studies are necessary to understand the mechanism underlying FO behaviors in rats subjected to encephalopathy.

Effects of Omega-3 on Neurodegenerative Diseases and Stroke

The polyunsaturated fatty acids (PUFAs), especially omega-3 (ω-3 PUFA), are among the most promising molecules in functional food science. There is evidence of health benefits with ω-3 PUFA intake in the settings of trauma; cardiovascular, immune, cognitive, and psychiatric disorders; and neurodegenerative diseases. ω-3 PUFA can be acquired by ingestion of flaxseed, chia seed, and canola oil, as well as coldwater fish, such as salmon, mackerel, herring, and tuna. It can also be supplemented as fish oil capsules containing EPA and DHA, which are the main representatives of the ω-3 PUFA family. ω-3 PUFA can act on four known cellular mechanisms: (1) alteration of cellular membrane properties, (2) anti-inflammatory action, (3) anti-oxidative activity, and (4) regulation of gene expression. This chapter is an endeavor to summarize the state-of-the-art details of the neuroprotective effects of these fatty acids on Parkinson’s disease, Alzheimer’s disease, and stroke through the review of both animal-model and human-based studies.